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Further Reading

Anthrax Vaccine Moves Into Clinical Trials

By Karen Fleming-Michael
Special to the American Forces Press Service

FORT DETRICK, Md., July 9, 2003 - The next-generation
anthrax vaccine, based on a decade of work at the U.S. Army
Medical Research Institute of Infectious Diseases, is now
moving into not one, but four clinical trials.

The group at the institute did the legwork for the current
vaccine candidates by singling out which protein in
Bacillus anthracis - the bacterium that causes anthrax -
signals the body to produce immunity to the disease.

Early studies established definitively that the protein
called "protective antigen" was just the component the
vaccine would require, said Dr. Arthur Friedlander, a
senior scientist at USAMRIID who directed the group's long-
term effort. After discovering the protein, researchers
took the gene that codes for protective antigen and used
recombinant DNA technology to try to produce the protective
antigen in three expression systems: bacteria, yeast and
viruses.

Ultimately, the team found bacteria was the best for
producing the protein, and decided to grow the protective
antigen in a non-disease causing strain of B. anthracis.
The resulting recombinant protective antigen, or rPA,
should provide a high degree of safety in a vaccine because
it's just one building block, a single protein of the
organism that can produce an immune response.

Researchers then proved it was effective in the best animal
model available, the non-human primate. "What we did was
identify it, purify it to a very high degree and showed
that this protein by itself was protective in the most
relevant animal model of human inhalational anthrax,"
Friedlander said.

To date, two clinical trials that use the B. anthracis-
based rPA are underway. VaxGen, based in Brisbane, Calif.,
started its clinical trials at Baylor College of Medicine,
Texas; Emory University School of Medicine in Atlanta;
Johns Hopkins University in Baltimore and Saint Louis
University Health Sciences Center. The test is under a
contract from the National Institute of Allergy and
Infectious Diseases.

In a collegial effort, the National Institute of Allergy
and Infectious Diseases, USAMRIID and the Joint Vaccine
Acquisition Program have undertaken a Phase I clinical
trial at the University of Maryland using a version of the
original USAMRIID formulation manufactured at the National
Cancer Institute Frederick, Md.

The University of Maryland trial will help advance the
development of the other vaccines, said Dr. Lydia Falk,
director of the Office of Regulatory Affairs, in the
Division of Microbiology and Infectious Diseases at the
National Institute of Allergy and Infectious Diseases.

"We can begin to compare the responses we see in humans to
what had been observed in animals," she said. "That's a
critical part of the development of these vaccines. The
more preliminary investigative work that we can do, the
more it benefits the entire field. Our hope is that the
information we gain will be able to add to those building
blocks that would lead to an accelerated development plan."

The formulation being used in that trial won't be pushed
toward Food and Drug Administration licensing. "The product
that is available and the one that was used during
USAMRIID's preclinical studies had the rPA protein in one
tube and an aluminum adjuvant in another tube, and before
you injected it, you mixed the two," Falk said. "That's not
an easy formulation to take to licensure." However this
trial design will determine the value of including an
adjuvant in the final vaccine formulation.

Two companies are currently using rPA grown in E. coli to
create their next generation anthrax vaccine candidates. An
rPA vaccine from the UK-based Avecia, under a contract with
the National Institute of Allergy and Infectious Disease,
will soon start Phase I clinical trials.

The second company, Dynport Vaccine Company, LLC, which
licensed its rPA product from Avant, began its Phase I
clinical trial April 28. The trial is being conducted by
the Henry M. Jackson Foundation in Rockville, Md., which
routinely pursues vaccines for HIV for the military.

Because the foundation had an HIV vaccine candidate that
used rPA as one of its two components "we decided to
reprioritize our activities and commit to evaluating this
protective antigen after the anthrax mail attacks in
October 2001," said Dr. Merlin Robb of the Henry M. Jackson
Foundation, the principal investigator for the foundation's
clinical trial. "(The rPA) was ready to go into humans to
evaluate it for an anthrax indication. We sensed that it
was a higher national priority."

Although the rPA vaccines are on an advanced development
path toward Food and Drug Administration licensure,
USAMRIID scientists still lend their expertise to vaccine
manufacturers and the National Institute of Allergy and
Infectious Diseases.

"Their contributions can't be overstated," said Dr. Ed
Nuzum, the project officer providing technical oversight
for the two National Institute of Allergy and Infectious
Diseases contracts with Avecia and VaxGen. "Because of the
work done at USAMRIID, as well as its counterpart in the
United Kingdom, the Defence Science and Technology
Laboratories, the rPA-based vaccine candidates are the most
advanced second generation anthrax vaccines."

USAMRIID's early development work regarding animal studies
and assay development will also be critical for developing
animal models for Food and Drug Administration approval
under the "Animal Rule." The rule, effective in July 2002,
permits use of data from animal studies when efficacy
studies of new drugs or biological products against
chemical, biological, radiological or nuclear substances in
humans is impossible because of the rarity of the disease
or because human exposure to potentially lethal agents,
like anthrax, is unethical.

"This is the first test case of the concept of licensing a
vaccine based on animal efficacy data and trying to
correlate that with the human immune response," Friedlander
said.

Nuzum said he thinks the rPA vaccines are potentially the
best vaccines to be going forward for licensure under the
animal rule largely because of the work done at USAMRIID
and DSTL. "The data, models and assays really are essential
to the foundation for the work we're doing now," he said.